Chromosomal instability accelerates the evolution of resistance to anti-cancer therapies

• Published in: Developmental cell Vol. 56; no. 17; pp. 2427 - 2439.e4
• Main Authors: Lukow, Devon A., Sausville, Erin L., Suri, Pavit, Chunduri, Narendra Kumar, Wieland, Angela, Leu, Justin, Smith, Joan C., Girish, Vishruth, Kumar, Ankith A., Kendall, Jude, Wang, Zihua, Storchova, Zuzana, Sheltzer, Jason M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.09.2021
• Subjects: Aneuploidy; cancer; Cell Line, Tumor; Chromosomal Instability - genetics; CIN; drug resistance; Drug Resistance - drug effects; Environment; evolution; Humans; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - pathology; Treatment Outcome; aneuploidy; CIN; cancer; evolution; drug resistance
• ISSN: 1534-5807; 1878-1551; 1878-1551
• DOI: 10.1016/j.devcel.2021.07.009

Aneuploidy is a ubiquitous feature of human tumors, but the acquisition of aneuploidy typically antagonizes cellular fitness. To investigate how aneuploidy could contribute to tumor growth, we triggered periods of chromosomal instability (CIN) in human cells and then exposed them to different culture environments. We discovered that transient CIN reproducibly accelerates the acquisition of resistance to anti-cancer therapies. Single-cell sequencing revealed that these resistant populations develop recurrent aneuploidies, and independently deriving one chromosome-loss event that was frequently observed in paclitaxel-resistant cells was sufficient to decrease paclitaxel sensitivity. Finally, we demonstrated that intrinsic levels of CIN correlate with poor responses to numerous therapies in human tumors. Our results show that, although CIN generally decreases cancer cell fitness, it also provides phenotypic plasticity to cancer cells that can allow them to adapt to diverse stressful environments. Moreover, our findings suggest that aneuploidy may function as an under-explored cause of therapy failure. [Display omitted] •Periods of chromosomal instability can accelerate acquisition of drug resistance•Drug-resistant cancer cells frequently harbor recurrent aneuploidies•Recapitulation of an aneuploidy in drug-naive cells is sufficient for resistance•Chromosomal instability correlates with poor therapeutic responses in human tumors Chromosomal instability (CIN) is a hallmark of cancer and is frequently found to correlate with aggressive disease. However, the role of CIN in driving tumor progression is poorly understood. Here, Lukow et al. demonstrate a role for CIN in promoting therapeutic resistance through the acquisition of specific aneuploidies.